The present invention relates to a muscarinic acetylcholine nervous system labeled compound, and more specifically to a muscarinic acetylcholine nervous system labeled compound for positron emission tomography (PET) measurement.
With an aging society, the increasing economic burden due to an increase in the number of people with dementia is becoming a social problem, and hence elucidation of the condition of dementia and development of effective anti-dementia drugs are needed.
The pathology of dementia is not yet clear, but research hitherto has suggested that deterioration of the functioning of the acetylcholine nervous system is one cause of dementia. Evaluation of the functioning of the acetylcholine nervous system thus plays a very important role in elucidating the condition of dementia and in developing anti-dementia drugs, and hence there are strong calls for the development of non-intrusive methods of carrying out such evaluation and of labeled compounds suitable for use in these methods.
A method in which positron emission tomography (hereinafter referred to as xe2x80x98PETxe2x80x99) measurements are carried out using a labeled compound possessing a positron-emitting nuclear species is known as a non-intrusive method for evaluating the functioning of the acetylcholine nervous system. In this method, acetylcholine nervous system receptors are labeled using the labeled compound, and xcex3-rays that are emitted upon positrons emitted from the emitting nuclear species combining with matter-constituting electrons and annihilation taking place are measured, thus measuring the distribution of the receptors.
[11C]N-methyl-4-piperidyl benzilate (hereinafter referred to as xe2x80x98[11C]4-NMPBxe2x80x99) has been proposed as a muscarinic acetylcholine nervous system labeled compound for use in such PET measurements. However, there have been problems such as the following with PET measurements using [11C]4-NMPB:
(i) the ionicity of [11C]4-NMPB is low in the blood, and hence the liposolubility is high, and thus the ability to migrate into tissue is good, but the amount of [11C]4-NMPB that binds non-specifically to muscarinic acetylcholine nervous system receptors in the tissue is high, and hence errors are prone to arising when measuring the amount of [11C]4-NMPB that binds specifically to the receptors;
(ii) [11C]4-NMPB has a structure for which optical isomers do not exist, and hence errors are prone to arising when measuring the amount of [11C]4-NMPB that binds specifically to muscarinic acetylcholine nervous system receptors;
(iii) the affinity of [11C]4-NMPB to the receptors is high and the dissociation constant (k4) is very low, and hence the movement of [11C]4-NMPB in the brain is prone to being affected by changes in the local blood flow amount, and thus in the case of a disease model or a condition accompanied by a drop in cerebral circulation, it is difficult to distinguish whether measurement results are due to genuine changes in the activity of the muscarinic acetylcholine nervous system receptors or merely due to changes in the local blood flow amount in the brain;
(iv) the affinity of [11C]4-NMPB to the muscarinic acetylcholine nervous system receptors is very high compared with that of acetylcholine, which is an intrinsic neurotransmitter, and hence it is difficult to measure competition on the receptors between acetylcholine that has been discharged from preganglionic nerves due to neurotransmission and the labeled compound.
Moving on, it is disclosed in Japanese Patent Application Laid-open No. 11-152270 that by using [11C](xc2x1)N-methyl-3-piperidyl benzilate (hereinafter referred to as xe2x80x98[11C](xc2x1)3-NMPBxe2x80x99), PET measurements can be carried out with higher precision than when [11C]4-NMPB is used. However, even using [11C](xc2x1)3-NMPB has still not been sufficient with regard to carrying out PET measurements with improved precision.
In view of the problems of the prior art described above, it is an object of the present invention to provide a muscarinic acetylcholine nervous system labeled compound that enables PET measurements to be carried out efficiently with improved precision and without there being influence from changes in the blood flow amount in the region of interest in the brain, a method of manufacturing the labeled compound, and a positron emission tomography measurement method using the labeled compound.
The present inventors carried out assiduous studies to attain the above object, and as a result discovered that the problems described above can be resolved by using an 11C-labeled benzilic acid alkylpiperidyl ester having a specific structure as a muscarinic acetylcholine nervous system labeled compound, thus arriving at the present invention.
Specifically, a muscarinic acetylcholine nervous system labeled compound for positron emission tomography measurement of the present invention is characterized by having a structure represented by undermentioned general formula (I): 
[in the formula, W represents one selected from the group consisting of groups represented by undermentioned formulae (II) and (III): 
(in the formulae, R represents one selected from the group consisting of an 11C-labeled ethyl group and an 11C-labeled propyl group), and in the case that W is a group represented by above-mentioned formula (II), above-mentioned formula (I) is the (+)-isomer].
Moreover, a method of manufacturing a muscarinic acetylcholine nervous system labeled compound for positron emission tomography measurement of the present invention is characterized by comprising a step of obtaining a compound represented by undermentioned formula (I): 
from an 11C-labeled alkyl halide represented by undermentioned formula (IV):
Rxe2x80x94Xxe2x80x83xe2x80x83(IV)
and a benzilic acid piperidyl ester represented by undermentioned formula (V): 
[In the formulae, R represents one selected from the group consisting of an 11C-labeled ethyl group and an 11C-labeled propyl group, X represents a halogen atom, Wxe2x80x2 represents one selected from the group consisting of a (+)3-piperidyl group and a 4-piperidyl group, and W represents one selected from the group consisting of groups represented by undermentioned formulae (II) and (III): 
(in the formulae, R represents one selected from the group consisting of an 11C-labeled ethyl group and an 11C-labeled propyl group).]
Furthermore, a positron emission tomography measurement method of the present invention comprises: a step of administering the above-mentioned labeled compound of the present invention to a subject, thus labeling muscarinic acetylcholine nervous system receptors of the subject with the labeled compound; and a step of measuring xcex3-rays emitted through the combination of positrons emitted from an emitting nuclear species possessed by the labeled compound and prescribed matter-constituting electrons.
According to the present invention, by using a labeled compound represented by above-mentioned formula (I), in PET measurements, the amount of xcex3-rays corresponding to specific binding between the labeled compound and the above-mentioned receptors can be measured with high precision without there being influence from changes in the blood flow amount. It thus becomes possible to obtain information on the acetylcholine nervous system in prescribed regions of interest in the brain with high precision. Moreover, the affinity of the labeled compound of the present invention to the receptors is lower than that of conventional labeled compounds, and binding of the labeled compound to the receptors and dissociation of the labeled compound from the receptors occurs in a relatively short time, and hence PET measurements can be carried out efficiently.